We propose to use systems approaches to attempt to delineate some of the components in the prion and dopple informational pathways. This includes cloning and characterizing modifier genes for prion and dopple activity (e.g., neurodegenerative diseases) and rigorous similarity searches of the emerging human and mouse sequence to identify other prion-like genes. We also propose to perturb the prion system, both in vivo and in vitro, genetically (knockouts, overexpression) and/or biologically (infection) to determine the quantitative interrelationships of the relevant gene products. We will use DNA array technologies and later proteomics technologies. In this manner we hope to gain insights into the prion informational pathways.